Introduction Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several molecules. Oncostatin M (OSM) is known to orchestrate hypoxia-modulated hepatic processes involving the hypoxia-inducible factor 1 (HIF-1) and has been recently proposed to act, although indirectly, as a pro-fibrogenic mediator. Aims This study has been designed to further investigate the possible pro-fibrogenic action of OSM in relation to experimental and human NAFLD/NASH and in order to elucidate whether this cytokine may also act directly on LX2 cells (as a model of activated human MFs) by modulating and sustaining selected pro-fibrogenic phenotypic responses. Materials and Methods In vivo and in vitro experiments were performed in order to analyze the expression of OSM and related receptor (OSMR) in two different murine model of progressive NAFLD/NASH (MCD and CDAA diets) and in human NASH patients. Moreover, the action of recombinant human OSM was tested on phenotypic responses of human LX2 cells. Results OSM and OSMR expression increases in two murine models of NAFLD as well as in patients with NASH. OSM stimulates migration in LX2 cells involving an early intracellular ROS generation and activation of Ras/Erk, JNK1/2, PI3K/Akt as well as of STAT1/STAT3 pathways and involvement of HIF-1; apocynin inhibited OSM-dependent migration, suggesting NADPH-oxidase as a major source of intracellular ROS; OSM-dependent motogenic action is exerted through a biphasic mechanism requiring early ROS generation and late HIF1-dependent expression and VEGF release. Conclusions OSM can be considered as a mediator potentially able to trigger and/or sustain MFs activation and likely the fibrogenic progression of NAFLD.
Oncostatin M, a novel profibrogenic mediator, is involved in the progression non-alcoholic fatty liver disease and stimulates migration of myofibroblasts
Foglia B;Novo E;Cannito S;Protopapa F;Bocca C;Rosso C;Bugianesi E;
2020-01-01
Abstract
Introduction Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several molecules. Oncostatin M (OSM) is known to orchestrate hypoxia-modulated hepatic processes involving the hypoxia-inducible factor 1 (HIF-1) and has been recently proposed to act, although indirectly, as a pro-fibrogenic mediator. Aims This study has been designed to further investigate the possible pro-fibrogenic action of OSM in relation to experimental and human NAFLD/NASH and in order to elucidate whether this cytokine may also act directly on LX2 cells (as a model of activated human MFs) by modulating and sustaining selected pro-fibrogenic phenotypic responses. Materials and Methods In vivo and in vitro experiments were performed in order to analyze the expression of OSM and related receptor (OSMR) in two different murine model of progressive NAFLD/NASH (MCD and CDAA diets) and in human NASH patients. Moreover, the action of recombinant human OSM was tested on phenotypic responses of human LX2 cells. Results OSM and OSMR expression increases in two murine models of NAFLD as well as in patients with NASH. OSM stimulates migration in LX2 cells involving an early intracellular ROS generation and activation of Ras/Erk, JNK1/2, PI3K/Akt as well as of STAT1/STAT3 pathways and involvement of HIF-1; apocynin inhibited OSM-dependent migration, suggesting NADPH-oxidase as a major source of intracellular ROS; OSM-dependent motogenic action is exerted through a biphasic mechanism requiring early ROS generation and late HIF1-dependent expression and VEGF release. Conclusions OSM can be considered as a mediator potentially able to trigger and/or sustain MFs activation and likely the fibrogenic progression of NAFLD.
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